The goal of this research is to explore whether gene expression in lung tissue is modulated by antioxidant status. Chronic Obstructive Pulmonary Disease (COPD) is characterized by the development of irreversible airflow limitation and is the fourth leading cause of mortality in the United States. The current understanding of COPD pathogenesis implicates an oxidant/antioxidant imbalance in disease susceptibility. Although 80-90% of COPD patients are current or former smokers, only 15% of the variation in lung function is explained by smoking parameters, thus it is clear that disease etiology involves other, undiscovered factors. Observational epidemiologic studies support the hypothesis that enhanced antioxidant defenses diminish oxidant burden in lung tissue thus mitigating tissue damage contributing to COPD onset and progression. Adaptive response to an exposure is reflected in gene expression patterns, and alterations in normal gene expression are evident in asymptomatic smokers and COPD patients. Altered gene expression patterns are expected to precede biochemical and tissue changes on disease development and progression pathways, thus investigations of modifiers of gene expression such as antioxidant status provide targets for transcription-level intervention to interrupt disease pathogenesis. We propose a two part study to investigate whether damage caused by oxidative stress is attenuated by higher antioxidant status. First, a double-blinded, placebo-controlled intervention study of antioxidant supplements will investigate whether supplements modulate gene expression of oxidant-related genes in lung epithelial cells of asymptomatic smokers. If antioxidant supplementation alters gene expression and therefore mitigates damage caused by cigarette smoking, then this would offer a simple, inexpensive way to reduce susceptibility to COPD. Second, an investigation of the dependency of expression of oxidant-related genes in COPD patients on systemic and tissue-specific antioxidant status, oxidative stress burden, and GOLD stage is proposed using samples from the Lung Tissue Research Consortium (LTRC). If lower antioxidant status is related to greater alteration of gene expression in COPD patients this may provide a target for further investigation of antioxidants'potential to slow progression of COPD. Understanding how antioxidant status and supplementation modulate gene expression in the lung will enhance our understanding of variation in the response to cigarette smoke exposure and disease states. The resulting knowledge may lead to a better understanding of disease susceptibility and progression and identify primary and secondary prevention opportunities. PUBLIC HEALTH RELEVANCE: "Gene Expression Effect of Antioxidant Supplementation on Epithelium of Lung:ExSEL" will improve understanding of the interaction between nutrition and the genome in disease development. The proposed study will investigate the potential of antioxidant supplements to function as novel, inexpensive preventives of COPD onset. The proposed research also seeks to understand whether a person's body level of antioxidants, which can be modified by dietary supplements, is related to severity of disease in Chronic Obstructive Pulmonary Disease (COPD) patients. Thus, the findings from this project may ultimately help to reduce the burden of disease by identifying novel therapies to prevent the onset and/or slow the progression of COPD. (End of Abstract)